MetaCyc Pathway: TCA cycle I (prokaryotic)
Inferred from experiment

Pathway diagram: TCA cycle I (prokaryotic)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: tricarboxylic acid cycle, citric acid cycle, Krebs cycle, Szent-Gyorgyi-Krebs cycle

Superclasses: Generation of Precursor Metabolites and EnergyTCA cycle

Some taxa known to possess this pathway include : Azotobacter vinelandii, Escherichia coli K-12 substr. MG1655

Expected Taxonomic Range: Archaea, Bacteria

General Background

The TCA pathway is a catabolic pathway of aerobic respiration that generates both energy and reducing power. In addition, it is also the first step in generating precursors for biosynthesis. The pathway is very common, and a variation of it exists in practically all aerobic living organisms [Krebs37, Krebs38, Krebs45].

The input to the cycle is acetyl-CoA, an activated form of acetate that is generated by the degradation of carbohydrates, fats and proteins. A common source of acetyl-coA is pyruvate, which is generated by glycolysis and converted to acetyl-CoA by the pyruvate dehydrogenase complex.

In every turn the TCA cycle converts one molecule of acetyl-CoA into two CO2 molecules, reduces a total of four molecules of either NAD+, NADP+, or quinone to NADH, NADPH and quinol, respectively, and phosphorylates one molecule of GDP to GTP.

The reduced molecules of NADH/NADPH/quinol that are formed by the TCA cycle serve as electron donors for oxidative phosphorylation (see for example aerobic respiration I (cytochrome c)). In that process the electrons flow to a terminal acceptor, powering on their way proton pumps that trasport protons across the cytoplasmic or mitochondrial membranes, generating a proton motive force (PMF). As the protons return to their original location, they power ATPase enzymes that phosphorylate ADP molecules to ATP. The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the TCA cycle, and oxidative phosphorylation equals about 30 ATP molecules in eukaryotes.

The name of the TCA (short for tricarboxylic acid) cycle is derived from the fact that the first step in the pathway is attachment of acetyl-coA to citrate, an acid with three carboxylate groups. The pathway is also known as the citric acid cycle, and as the Szent-Gyorgyi-Krebs cycle (or just the Krebs cycle), named after the scientists who described it.

Some organisms possess a truncated version of the TCA cycle, known as the glyoxylate cycle, that converts acetyl-CoA to biosynthetic intermediates without the loss of CO2 [Walsh84, Nimmo87, Holms87].

About This Pathway

This is a common variation of the pathway that occurs in many bacteria and archaea. There are a few small differences between this prokaryotic version of the cycle and the version found in most eukaryotes (see TCA cycle II (plants and fungi)). In this pathway, an NADP-dependent enzyme ( EC catalyzes the dehydrogenation of D-threo-isocitrate to 2-oxoglutarate, while eukaryotes employ an NAD+-dependent enzyme ( EC Another difference is that while in most eukaryotes the conversion of (S)-malate to oxaloacetate is catalyzed only by an NAD-dependent enzyme ( EC, prokaryotes that employ this variation of the TCA cycle possess an alternative quinone-dependent enzyme ( EC

While the pathway is most common in heterotrophic bacteria and arachaea, there is evidence for its presence in some facultatively autotrophic archaea when growing under heterotrophic conditions.

In Escherichia coli, when acetate is the carbon source, citrate synthase is rate-limiting for the TCA cycle [Walsh85, Walsh87].

Superpathways: superpathway of glyoxylate bypass and TCA, superpathway of glycolysis, pyruvate dehydrogenase, TCA, and glyoxylate bypass

Variants: partial TCA cycle (obligate autotrophs), TCA cycle II (plants and fungi), TCA cycle III (animals), TCA cycle IV (2-oxoglutarate decarboxylase), TCA cycle V (2-oxoglutarate:ferredoxin oxidoreductase), TCA cycle VII (acetate-producers), TCA cycle VIII (helicobacter)

Unification Links: AraCyc:TCA, EcoCyc:TCA

Revised 19-Dec-2011 by Caspi R, SRI International


Baldwin81a: Baldwin JE, Krebs H (1981). "The evolution of metabolic cycles." Nature 291(5814);381-2. PMID: 7242661

Holms87: Holms WH (1987). "Control of flux through the citric acid cycle and the glyoxylate bypass in Escherichia coli." Biochem Soc Symp 1987;54;17-31. PMID: 3332993

Krebs37: Krebs HA, Johnson WA (1937). "Acetopyruvic acid (αγ-diketovaleric acid) as an intermediate metabolite in animal tissues." Biochem J 31(5);772-9. PMID: 16746397

Krebs38: Krebs HA, Salvin E, Johnson WA (1938). "The formation of citric and α-ketoglutaric acids in the mammalian body." Biochem J 32(1);113-7. PMID: 16746585

Krebs45: Krebs HA, Eggleston LV (1945). "Metabolism of acetoacetate in animal tissues. 1." Biochem J 39(5);408-19. PMID: 16747930

Nimmo87: Nimmo HG, Borthwick AC, el-Mansi EM, Holms WH, MacKintosh C, Nimmo GA (1987). "Regulation of the enzymes at the branchpoint between the citric acid cycle and the glyoxylate bypass in Escherichia coli." Biochem Soc Symp 1987;54;93-101. PMID: 3333001

Walsh84: Walsh K, Koshland DE (1984). "Determination of flux through the branch point of two metabolic cycles. The tricarboxylic acid cycle and the glyoxylate shunt." J Biol Chem 1984;259(15);9646-54. PMID: 6378912

Walsh85: Walsh K, Koshland DE (1985). "Characterization of rate-controlling steps in vivo by use of an adjustable expression vector." Proc Natl Acad Sci U S A 1985;82(11);3577-81. PMID: 3889909

Walsh87: Walsh K, Schena M, Flint AJ, Koshland DE (1987). "Compensatory regulation in metabolic pathways--responses to increases and decreases in citrate synthase levels." Biochem Soc Symp 1987;54;183-95. PMID: 3332995

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Al12: Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM (2012). "Identity and function of a large gene network underlying mutagenic repair of DNA breaks." Science 338(6112);1344-8. PMID: 23224554

Allen64: Allen, S.H., Kellermeyer, R.W., Ssjernholm, R.L., Wood, H.G. (1964). "Purification and properties of enzymes involved in the propionic acid fermentation." J Bacteriol 87;171-87. PMID: 14102852

Allison88: Allison N, Williams CH, Guest JR (1988). "Overexpression and mutagenesis of the lipoamide dehydrogenase of Escherichia coli." Biochem J 256(3);741-9. PMID: 3066354

Alwine73: Alwine JC, Russell RM, Murray KN (1973). "Characterization of an Escherichia coli mutant deficient in dihydrolipoyl dehydrogenase activity." J Bacteriol 115(1);1-8. PMID: 4197899

Amarneh05: Amarneh B, Vik SB (2005). "Direct transfer of NADH from malate dehydrogenase to complex I in Escherichia coli." Cell Biochem Biophys 42(3);251-61. PMID: 15976458

Anderson88: Anderson DH, Duckworth HW (1988). "In vitro mutagenesis of Escherichia coli citrate synthase to clarify the locations of ligand binding sites." J Biol Chem 1988;263(5);2163-9. PMID: 3276685

Apostolakos82: Apostolakos D, Menter PA, Rampsch BJ, Reeves HC, Birge EA "Genetic map position of the cistron coding for isocitrate dehydrogenase in Escherichia coli K-12." Current Microbiology 1982;7:45-47.

Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699

Bailey99: Bailey DL, Fraser ME, Bridger WA, James MN, Wolodko WT (1999). "A dimeric form of Escherichia coli succinyl-CoA synthetase produced by site-directed mutagenesis." J Mol Biol 285(4);1655-66. PMID: 9917403

Banerjee05: Banerjee S, Nandyala A, Podili R, Katoch VM, Hasnain SE (2005). "Comparison of Mycobacterium tuberculosis isocitrate dehydrogenases (ICD-1 and ICD-2) reveals differences in coenzyme affinity, oligomeric state, pH tolerance and phylogenetic affiliation." BMC Biochem 6;20. PMID: 16194279

Barker00: Barker HC, Kinsella N, Jaspe A, Friedrich T, O'Connor CD (2000). "Formate protects stationary-phase Escherichia coli and Salmonella cells from killing by a cationic antimicrobial peptide." Mol Microbiol 35(6);1518-29. PMID: 10760151

Beh93: Beh M, Strauss G, Huber R, Stetter K-O, Fuchs G (1993). "Enzymes of the reductive citric acid cycle in the autotrophic eubacterium Aquifex pyrophilus and in the archaebacterium Thermoproteus neutrophilus." Arch Microbiol 160: 306-311.

Bell89: Bell PJ, Andrews SC, Sivak MN, Guest JR (1989). "Nucleotide sequence of the FNR-regulated fumarase gene (fumB) of Escherichia coli K-12." J Bacteriol 1989;171(6);3494-503. PMID: 2656658

Bennett95: Bennett B, Gruer MJ, Guest JR, Thomson AJ (1995). "Spectroscopic characterisation of an aconitase (AcnA) of Escherichia coli." Eur J Biochem 233(1);317-26. PMID: 7588761

Berkemeyer98: Berkemeyer M, Scheibe R, Ocheretina O (1998). "A novel, non-redox-regulated NAD-dependent malate dehydrogenase from chloroplasts of Arabidopsis thaliana L." J Biol Chem 273(43);27927-33. PMID: 9774405

Bernstein78: Bernstein LH, Grisham MB, Cole KD, Everse J (1978). "Substrate inhibition of the mitochondrial and cytoplasmic malate dehydrogenases." J Biol Chem 253(24);8697-701. PMID: 214429

Bild80: Bild GS, Janson CA, Boyer PD (1980). "Subunit interaction during catalysis. ATP modulation of catalytic steps in the succinyl-CoA synthetase reaction." J Biol Chem 255(17);8109-15. PMID: 6997289

Birney96: Birney M, Um HD, Klein C (1996). "Novel mechanisms of Escherichia coli succinyl-coenzyme A synthetase regulation." J Bacteriol 178(10);2883-9. PMID: 8631677

Birney97: Birney M, Um H, Klein C (1997). "Multiple levels of regulation of Escherichia coli succinyl-CoA synthetase." Arch Biochem Biophys 347(1);103-12. PMID: 9344470

BochudAllemann02: Bochud-Allemann N, Schneider A (2002). "Mitochondrial substrate level phosphorylation is essential for growth of procyclic Trypanosoma brucei." J Biol Chem 277(36);32849-54. PMID: 12095995

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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